医学
主旨
伊马替尼
癌症研究
转移
抗药性
间质瘤
间质细胞
肿瘤科
自噬
癌症
内科学
细胞凋亡
生物
微生物学
髓系白血病
生物化学
作者
Xiangfei Sun,Xiao-feng Gao,Kuntang Shen
出处
期刊:PubMed
日期:2019-09-25
卷期号:22 (9): 886-890
标识
DOI:10.3760/cma.j.issn.1671-0274.2019.09.014
摘要
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.胃肠间质瘤(GIST)是胃肠道最常见的间叶组织来源肿瘤。手术完整切除是唯一的根治办法,但术后常常发生复发和转移。目前,治疗复发、转移和不可切除GIST的一线药物是甲磺酸伊马替尼(IM),超过80%的患者可以从IM治疗中获益,但是一半患者在治疗后2年内会发生进展,而继发性耐药则是造成疾病进展的一个主要原因。因此,对继发性耐药机制的深入理解,将指导我们在未来制定个性化治疗方案。本文从基因的改变、信号传导通路的异常激活、细胞自噬、细胞凋亡以及药物浓度等方面阐述IM继发性耐药机制,发现单一药物治疗IM继发性耐药患者具有一定的局限性,而使用IM联合下游信号分子抑制剂、自噬抑制剂、1型胰岛素样生长因子受体(IGF-1R)抑制剂、热休克蛋白90(HSP90)抑制剂、细胞毒性T淋巴细胞相关抗原4(CTLA-4)抗体和线粒体抑制剂为我们提供了新的治疗思路。但是这些联合治疗方案还在研究阶段,安全性和有效性还需进一步的临床试验去证实。对耐药机制的深入研究,将会为目前严峻的耐药问题提供更多解决的方向。.
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